The hydroxypyrimidinone carboxamides disclosed in WO03/035077 and the hydroxy-tetrahydropyridopyrimidinone carboxamides and related carboxamides disclosed in WO 2004/058756 are HIV integrase inhibitors useful for the treatment of HIV infection and AIDS. Certain of these carboxamide compounds exhibit relatively low aqueous solubility which can lead to poor absorption of the compound in the gastrointestinal (GI) tract following oral administration. The solubility of these compounds can be improved by administering the drugs in the form of base salts (i.e., the salts formed by reaction of the compounds with basic salts such as metal hydroxides), but the solubility of some of the resulting salts can change as a function of pH. More particularly, the base salts can be comparatively soluble in neutral or basic aqueous media, but can convert to less soluble forms under acidic conditions. Representative of such salts is the potassium salt of Compound A:
The potassium salt of Compound A is relatively soluble in neutral and basic aqueous solutions, but in acidic solutions it tends to disproportionate to the relatively insoluble free base form. When the Compound A K salt is administered orally in a solid dosage form, the compound can exhibit poor absorption into the systemic circulation due to the lost or significantly reduced solubility of the salt in the acidic conditions typically encountered in the stomach.
Satisfactory oral bioavailability can be achieved by formulating these salts with an antinucleating agent. For example, compressed tablet formulations of the Compound A K salt containing hydroxypropylmethylcellulose (e.g., HPMC 2910) as the antinucleating agent have exhibited improved solubility in in vitro dissolution tests and improved pharmacokinetics (PK) in animal studies compared to analogous formulations not containing the antinucleating agent. Orally administered tablet formulations of the Compound A K salt with HPMC have also afforded satisfactory pharmacokinetics (PK) in humans. It is believed that the antinucleating agent employed in these formulations can sufficiently inhibit and/or delay precipitation (or, stated another way, can provide prolonged supersaturation) of the drug compound under the acidic conditions of the stomach or the intestine, so as to permit the drug to be more efficiently absorbed into circulation.
On the other hand, the solid dosage formulations of the compound salts containing an antinucleating agent can have a relatively rapid absorption of the compound into the systemic circulation (i.e., a relatively short Tmax=the postdose time to Cmax, the maximum concentration of the compound in the plasma) and can be followed by a rapid decline. For example, the compressed tablet HPMC-containing formulations of Compound A K salt noted in the preceding paragraph have exhibited relatively high Cmax values, short Tmax values (e.g., from about 30 to 90 minutes) and relatively low plasma concentrations thereafter. High peak to trough plasma concentration ratios can be associated with adverse events, and low plasma concentrations subsequent to Tmax can result in little to no absorption of the drug outside the stomach and prior to elimination of the drug from the gastrointestinal tract (i.e., little or no absorption in the small intestine or colon). Accordingly, there exists a need for oral solid dosage formulations of these compounds which can control the release of the compound in a manner that provides an altered PK profile (i.e., a longer Tmax, a lower peak to trough plasma concentration ratio, and/or higher minimum plasma concentrations following Tmax) relative to that achieved by the antinucleating agent-based solid dosage formulations.